Icariin and its Derivative Icariside II Extend Healthspan via Insulin/IGF-1 Pathway in C. elegans

Compounds that delay aging might also postpone age-related diseases and extend healthspan in humans. Icariin is a flavonol extracted from several plant species of the Epimedium family. The icariin and its metabolic derivatives have been shown to exert wide protective effects in age-related diseases. However, whether icariin and its derivatives have the potency of delaying aging remains unclear. Here, we report that icariin and its derivative icariside II extend C. elegans lifespan. Using HPLC, we found high level of icariside II in the animals treated with icariin, suggesting icariside II is the bioactive form in vivo of icariin. Icariside II also increased the thermo and oxidative stress tolerance, slowed locomotion decline in late adulthood and delayed the onset of paralysis mediated by polyQ and Aβ1–42 proteotoxicity. The lifespan extension effect of icariside II is dependent on the insulin/IGF-1 signaling (IIS) since the daf-16(mu86) and daf-2(e1370) failed to show any lifespan extension upon icariside II treatment. Consistently, icariside II treatment upregulates the expression of DAF-16 targets in the wild-type. Moreover, our data suggests that the heat shock transcription factor HSF-1 has a role in icariside II-dependent lifespan extension further implicating the IIS pathway. In conclusion, we demonstrate a novel natural compound, icariside II as the bioactive form of icariin, extends the healthspan via IIS pathway in C. elegans

Icariside II Induces Apoptosis in U937 Acute Myeloid Leukemia Cells: Role of Inactivation of STAT3-Related Signaling

Background: The aim of this study is to determine anti-cancer effect of Icariside II purified from the root of Epimedium koreanum Nakai on human acute myeloid leukemia (AML) cell line U937. Methodology/Principal Findings Icariside II blocked the growth U937 cells in a dose- and time-dependent manner. In this anti-proliferation process, this herb compound rendered the cells susceptible to apoptosis, manifested by enhanced accumulation of sub-G1 cell population and increased the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Icariside II was able to activate caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) in a time-dependent manner. Concurrently, the anti-apoptotic proteins, such as bcl-xL and survivin in U937 cells, were downregulated by Icariside II. In addition, Icariside II could inhibit STAT3 phosphorylation and function and subsequently suppress the activation of Janus activated kinase 2 (JAK2), the upstream activators of STAT3, in a dose- and time-dependent manner. Icariside II also enhanced the expression of protein tyrosine phosphatase (PTP) SH2 domain-containing phosphatase (SHP)-1, and the addition of sodium pervanadate (a PTP inhibitor) prevented Icariside II-induced apoptosis as well as STAT3 inactivation in STAT3 positive U937 cells. Furthermore, silencing SHP-1 using its specific siRNA significantly blocked STAT3 inactivation and apoptosis induced by Icariside II in U937 cells. Conclusions/Significance: Our results demonstrated that via targeting STAT3-related signaling, Icariside II sensitizes U937 cells to apoptosis and perhaps serves as a potent chemotherapeutic agent for AML

Ikarizid II oldhatóságának növelése tejsavó proteinnel: Solubility increment of Icariside II with whey protein

Recent studies have shown a great interest in Icariside II (ICS) due to its use for treating properties in anti-cancer research, delays the Alzheimer disease, and it’s used to treat erectile dysfunction. Same as other natural agents, the greatest disadvantage of the ICS is its poor water solubility, consequently its bioavailability. Formation of complexes with protein is a widely used technique for the solubility increment of the small hydrophobic molecules. The purpose of the study is to improve the water solubility of ICS by forming the Icariside II -whey protein concentrate (WPC) complex. The newly formed bonds between the ICS and WPC were studied. In order to observe the solubility, increment the complexes with different mole rates were spray dried. The characterization shows that the solubility of Icariside II increased, the greatest results at ICS 2:1 WPC mole rates were observed. Kivonat A kutatások az ikarizid II-ról (ICSII) az utóbbi években kimutatták, hogy gátolja a rákos sejtek kialakulását, lassítja az Alzheimer kór előrehaladását, illetve gyógyítja a férfi merevedési diszfunkciót. Mint számos természetes hatóanyagnak, az ICSII is hátránya, hogy a vízben való oldhatósága rendkívül alacsony ezáltal biohasznosulása is. A proteinnel való komplexálás egy széles körben alkalmazott technika a kis molekulatömegű hidrofób molekulák oldhatóságának növelésére. A kutatás célja a tejsavó proteinnel (WPC) komplexálni az Ikarizid II-del, így növelni ennek az víz oldhatóságát. A kutatás során vizsgáltuk a WPC és a ICSII közötti kapcsolódás milyenségét, illetve a WPC hatását a ICSII oldhatóságára, ennek érdekében különböző mól arányú komplexeket előállítva használva a porlasztva szárítás technológiáját. A termékek jellemzése során kiderült, hogy a komplexálási művelet sikeresen növelte az Ikarizid II oldhatóságát, illetve, hogy ICS 2:1 WPC mólarány esetében volt a legnagyobb a vízoldhatósá

UPLC-MS/MS method for Icariin and metabolites in whole blood of C57 mice: development, validation, and pharmacokinetics study

Icariin, a Chinese medicinal herb with significant effects on Alzheimer’s disease, lacks pharmacokinetic data in mice. To address this, a UPLC-MS/MS method was developed and validated for quantifying Icariin and its metabolites, Icariside I and Icariside II, in the whole blood of mice. The method processed micro-whole blood from serial collections of the same C57 mouse, with well-fitted linearity (0.25–800 ng mL−1) and intra- and inter-day precision and accuracy within 15%. Short-time and autosampler stability were verified, with acceptable extraction recoveries and matrix effects over 74.55%. After intravenous administration (15 mg kg−1) of Icariin in C57 mice, Icariside I and Icariside II were detected within 2 min. However, after the intragastric administration (30, 90, and 150 mg kg−1) of Icariin in C57 mice, Icariin and Icariside I were not detected, and Icariin was rapidly converted into Icariside II. Furthermore, the Cmax and AUC0-t of three doses (30, 90, and 150 mg kg-1) of Icariside II increased as the dose increased. In conclusion, this method improves the traditional method of collecting only one blood sample from each mouse, detecting Icariin and its metabolites in the whole blood of mice, especially for serial collection of micro-whole blood

Traditional Chinese Medicine Therapy for Targeting Osteoblastogenesis

Osteoblasts are derived from bone marrow mesenchymal stem cell (BMSC) precursors, which differentiate into mature osteoblasts and mediate bone formation. This process is called osteoblastogenesis. A deficiency in osteoblastogenesis of BMSCs can result in bone-related diseases including osteoporosis. Thus, developing drugs for targeting osteoblastogenesis from BMSCs has become one of the therapeutic strategies for osteoporosis. In China, kidney-nourishing Chinese herbal drugs such as ER-Zhi-Wan have been believed to be potential for treating osteoporosis through targeting osteoblast proliferation and differentiation. The key pathways for regulating osteoblastogenesis include canonical and noncanonical Wnt pathway, semaphorin-mediated pathway, and MAPK-mediated BMP2-Smad pathway. Some natural products have been confirmed to regulate more than one pathway and exert multi-target effect through the use of one compound or combined use of more than two compounds, such as wedelolactone and oleonuezhenide. In addition, tissue engineering provides a promising strategy in the field for targeting osteoblastogenesis. New types of biomaterials including hydroxyapatite (HAp) combined with Chinese medicine can exert enhanced effect on osteoblastogenesis and provide new therapy for treating osteoporosis

Is there a role for stem cell therapy in erectile dysfunction secondary to cavernous nerve injury? Network meta-analysis from animal studies and human trials

Introduction: We carried out systematic review and network meta-analysis to investigate the role of stem cell therapy (SCT) in the management of erectile dysfunction (ED) secondary to cavernous nerve injury in rats and post-radical prostatectomy (RP) in humans. Patients and Methods: The protocol was registered with PROSPERO database. We searched studies analyzing the efficacy of SCT for ED due to bilateral cavernous nerve injury (BCNI) in rats using Healthcare Databases Advanced Search (HDAS) Export software (MEDLINE,EMBASE, Scopus) from inception to September 2020. The outcome measurements, for 29 animal studies, were intracavernosal pressure (ICP), ICP/MAP (mean arterial pressure) ratio, and histological/molecular changes. All three available human trials evaluating SCT in post-RP ED were assessed for International Index for Erectile Function (IIEF) Score and Erection Hardness Score (EHS). Results: For ICP measurement, animal studies were divided into adipose-derived stem cells (ADSCs) subgroup and bone marrow–derived stem cells (BMSCs) subgroup. Pooled analysis of these studies showed a beneficial effect of SCT in improving erectile function in rats with BCNI using network meta-analysis (95% confidence interval, CI; p < 0.001). There was an increase in ICP/MAP ratio in stem cell groups (including co-intervention) compared with control BCNI group. Histological and molecular evaluation of penile tissue revealed an increase in neuronal nitric oxide synthase (nNOS), smooth muscle content, and anti-apoptotic activity. Human trials revealed improved IIEF (70–150% from baseline at 6 months) and EHS (80–200% from baseline). Conclusion: Our results confirm that SCT does improve the erectile function in rats having cavernous nerve injury. Similarly, early human results have shown promising results

Polyphenols for Cancer Treatment or Prevention

Polyphenols are commonly found in fruits and vegetables, and have been suggested to have protective effects against chronic diseases, such as cancers. They are a diverse group of molecules, many of which possess antioxidant, anti-inflammatory, epigenetic, drug sensitization, and/or modulation of xenobiotic metabolizing enzyme properties. However, there is mixed evidence regarding their protective effects with respect to various cancers. Some of this controversy may be due to the combination of polyphenols administered, synergistic effects of accompanying compounds, bio-accessibility, bioavailability, effect of gut microbiota, and the type of cancer investigated. The purpose of this Special Issue is to present the recent evidence for the effect of polyphenol intake on cancer, as well as mechanisms of action. This Special Issue, entitled "Polyphenols for Cancer Treatment or Prevention", welcomes manuscript submissions of original research, meta-analyses, or reviews of the scientific literature. Authors should focus their manuscripts on polyphenol bioactives or dietary patterns naturally rich in polyphenols that have been identified and used for the prevention and or treatment of cancer

Icariside II Ameliorates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Inhibiting the Amyloidogenic Pathway: Involvement of BDNF/TrkB/CREB Signaling and Up-Regulation of PPARα and PPARγ in Rats

Chronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline of vascular dementia (VD) as it is conducive to induce beta-amyloid (Aβ) aggregation. Icariside II (ICS II), a plant-derived flavonoid compound, has showed neuroprotective effect on animal models of Alzheimer’s disease (AD) by decreasing Aβ levels. Here, we assessed the effect of ICS II on CCH-induced cognitive deficits and Aβ levels in rats, and the possible underlying mechanisms were also explored. It was disclosed that CCH induced by bilateral common carotid artery occlusion (BCCAO) caused cognitive deficits, neuronal injury and increase of Aβ1-40 and Aβ1-42 levels in the rat hippocampus, while oral administration of ICS II for 28 days abolished the above deficits in the hippocampus of BCCAO rats. Meanwhile, ICS II significantly decreased the expression of beta-amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1), as well as increased the expression of a disintegrin and metalloproteinase domain 10 (ADAM10) and insulin-degrading enzyme (IDE). ICS II also activated peroxisome proliferator-activated receptor (PPAR)α and PPARγ, enhanced the expression of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), levels of Akt and cAMP response element binding protein (CREB) phosphorylation. Together, these findings suggested that ICS II attenuates CCH-induced cognitive deficits by inhibiting the amyloidogenic pathway via involvement of BDNF/TrkB/CREB signaling and up-regulation of PPARα and PPARγ in rats

Icariside II, a Phosphodiesterase-5 Inhibitor, Attenuates Beta-Amyloid-Induced Cognitive Deficits via BDNF/TrkB/CREB Signaling

Background/Aims: Icariside II (ICS II) is an active component from Epimedium brevicornum, a Chinese medicine extensively used in China. Our previous study has proved that ICS II protects against learning and memory impairments and neuronal apoptosis in the hippocampus induced by beta-amyloid25-35 (Aβ25-35) in rats. However, its in-depth underlying mechanisms remain still unclear. Hence this study was designed to explore the potential underlying mechanisms of ICS II by experiments with an in vivo model of Aβ25-35-induced cognitive deficits in rats combined with a neuronal-like PC12 cells injury in vitro model. Methods: The cognitive deficits was measured using Morris water maze test, and apoptosis, intracellular reactive oxygen species (ROS) and mitochondrial ROS levels were detected by TUNEL, DCFH-DA and Mito-SOX staining, respectively. Expression of Bcl-2, Bax, brain derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and cAMP response element binding (p-CREB) and active-Caspase 3 levels were evaluated by Western blot. Results: It was found that ICS II, a phosphodiesterase-5 inhibitor, significantly attenuated cognitive deficits caused by Aβ25-35 injection in rats, and ICS II not only significantly enhanced the expression of BDNF and TrkB, but also activated CREB. Furthermore, ICS II also significantly abrogated Aβ25-35-induced PC12 cell injury, and inhibited Aβ25-35-induced intracellular reactive oxygen species (ROS) overproduction, as well as mitochondrial ROS levels. In addition, ICS II up-regulated the expressions of BDNF and TrkB consistent with the findings in vivo. ANA-12, a TrkB inhibitor, blocked the neuroprotective effect of ICS II on Aβ25-35-induced neuronal injury. Conclusion: ICS II mitigates Aβ25-35-induced cognitive deficits and neuronal cell injury by upregulating the BDNF/TrkB/CREB signaling, suggesting that ICS II can be used as a potential therapeutic agent for dementia, such as Alzheimer’s disease